Proopiomelanocortin (POMC), a neuropeptide, is the precursor for a variety of bioactive peptides such as ACTH, alpha, beta and gamma melanotropins, beta-lipotropin and beta-endorphin, each of which has diverse effects on various tissues. The POMC derived peptides, MSH and ACTH, are classically thought of as melanotropins or corticotropins, respectively. The melanotropins, whose biological effects on pigmentation were recognized earlier and studied extensively in lower vertebrates, are now known not only to regulate pigmentation but also to function as immunomodulators of inflammation and neurotransmitters. POMC is synthesized not only in the pituitary gland, the best known source, but also in many extrapituitary tissues such as other parts of the brain, testis, ovary, spleen, various types of lymphocytes and, of importance to our proposal, the skin. We have shown by immunocytochemical and northern blot analyses the presence of POMC and its derivative peptides in murine epidermis. Its origin seems to be Thy-I + dendritic cells, a population of bone marrow derived T lymphocytes found only in mouse epidermis. Recently we were the first to demonstrate that normal human melanocytes synthesize de novo and express POMC, alpha-MSH and ACTH, both in vitro and in an in vivo model. We postulate that alpha-MSH in epidermal melanocytes functions in a variety of ways, such as an autocrine factor to enhance melanogenesis and as a paracrine factor to modulate the intensity of the inflammatory reaction. alpha-MSH in vitro is mitogenic and melanogenic to human melanocytes, and seems to be a transducer of the effects of ultraviolet light. We and others have shown that the POMC peptides have potent anti-inflammatory properties. We postulate that POMC derived peptides might function to counterbalance the inflammatory effects of cytokines such as IL-1 and eicosanoids like prostaglandins and leukotrienes. In this proposal we will analyze the expression of POMC and its derivative peptides and determine first how the POMC gene is regulated at the RNA and protein levels under normal conditions in isolated human epidermal cells, specifically melanocytes and keratinocytes. We have available cultured skin substitutes (CSS). In organotypic culture or grafted on athymic mice we also will examine the effect of cell-cell interaction on the expression of POMC and Ths peptides. The proposed study on POMC peptides in the skin and their regulation by cytokines and by UV light will serve as a basis for future studies on cell-cell interaction in the epidermis; the role of neuropeptides - in the regulation of epidermal functions such as pigmentation and the inflammatory response. Such data will clarify our concepts on how the epidermis functions and provide an expanded basis for understanding clinical phenomena such as post inflammatory hyperpigmentation commonly observed in grafts used to treat burn patients.